Decomposing Interaction and Mediating Effects of Race/Ethnicity and Circulating Cystatin C on Cognitive Status in the United States Health and Retirement Study

Background and objectivesElevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia. MethodsIn a pooled cross-sectional sample of the Health and Retirement Study (n=9,921), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24mg/L versus <1.24mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, and other biomarkers. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity. ResultsOverall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.4; 95%CI: 1.2, 1.8). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 1.7 (95% CI: -0.2, 3.7), the attributable proportion was 0.2 (95%CI: 0.0, 0.5), and the synergy index was 1.4 (95% CI: 1.0, 2.0) in a fully-adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0%, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 9% (95% CI: -4%, 23%). Analyses for Hispanic relative to non-White participants suggested moderation by race/ethnicity, but not mediation. DiscussionElevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White.